Since the initial discovery of ?? cells 30 years ago, non-classical MHC molecules have been proposed as antigens or antigen presenting molecules for these cells. In the intervening years, individual T cell clones have been identified with reactivity to CD1 and TL molecules but MHC reactivity has not been shown for populations of ?? cells. Recent data from two groups has now shown that the V?1+ TCR from human peripheral blood and intestinal ?? cells can directly bind to CD1d-?GalCer and CD1d-sulfatide. Interestingly, the V?1+ TCR is also used by epidermal-resident ?? cells in both human and mouse skin. CD1 expression is upregulated on epidermal cells during skin inflammation and disease and the epidermis is a rich source of lipids and skin oils. This raises the possibility tha CD1-lipid reactivity may be characteristic of all V?1+ T cells, including those that are resident i the epidermis. We propose to test the hypothesis that CD1-skin lipid antigens can provide a stress-signal of damage or disease in the epidermis to neighboring V?1+ T cells to activate their wound healing functions. We will test this hypothesis by determining if the human or mouse V?1+ TCR can interact with CD1-lipid antigens and by investigating whether CD1d expression during wound healing impacts epidermal ?? cell wound healing responses. If found to be a prototypic stress-signal for ?? cell activation, CD1 or skin lipids may then be considered as targets in future strategies to improve healing of chronic wounds as well as other skin inflammatory or autoimmune diseases.